Stable pharmaceutical composition for oral administration

Abstract

Provided is a stable pharmaceutical composition for oral administration comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide (hereinafter referred to as compound A) or a pharmaceutically acceptable salt thereof, wherein the generation of related substances during storage is inhibited. In the stable pharmaceutical composition for oral administration, the proportion of crystals of compound A or a pharmaceutically acceptable salt thereof is 60% or more with respect to the total amount of compound A or a pharmaceutically acceptable salt thereof.

1 . A pharmaceutical composition for oral administration comprising:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate and a pharmaceutical additive,   wherein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 62% or more with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition, and   wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week.   
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 90% by weight. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, calcium stearate, and talc. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical additive is D-mannitol. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical additive is lactose. 
     
     
         7 . The pharmaceutical composition according to  claim 3 , wherein the pharmaceutical additive is D-mannitol. 
     
     
         8 . The pharmaceutical composition according to  claim 6 , wherein a total content of lactose is 50% by weight to 70% by weight with respect to a total weight of the pharmaceutical composition. 
     
     
         9 . The pharmaceutical composition according to  claim 5 , wherein a total content of D-mannitol is 50% by weight to 70% by weight with respect to a total weight of the pharmaceutical composition. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , which is a tablet. 
     
     
         11 . A tablet comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate and a pharmaceutical additive,
 herein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 62% or more with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition,   wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 90% by weight, and   wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week.   
     
     
         12 . The tablet according to  claim 11 , wherein the pharmaceutical additive is lactose. 
     
     
         13 . The tablet according to  claim 11 , wherein the pharmaceutical additive is D-mannitol. 
     
     
         14 . A pharmaceutical composition for oral administration comprising:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutical additive,   wherein the pharmaceutical composition exhibits a loss on drying of 2.0% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,   wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and   wherein the high-performance liquid chromatography method is performed under following conditions: 
 a Kinetex XB-C18 column, particle size: 2.6 µm, 4.6 mm (an inner diameter) x 75 mm; 
 a column temperature maintained at 40° C.; 
 a mobile phase A of a perchlorate solution (pH 2.2); 
 a mobile phase B of an acetonitrile solution; 
 a sample solution having a sample concentration of 0.8 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 a standard solution having a standard solution concentration of 0.008 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and 
 a gradient of the mobile phase A and mobile phase B is as follows: 
 (a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B; 
 (b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B; 
 (c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B; 
 (d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B; 
 (e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B; 
 (f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and 
 (g) from 26.1 minutes to 30 minutes since sample injection, 96% mobile phase A and 4% mobile phase B. 
 
   
     
     
         15 . The pharmaceutical composition according to  claim 14 , comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         16 . The pharmaceutical composition according to  claim 14 , wherein a content of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 10% by weight to 40% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         17 . The pharmaceutical composition according to  claim 14 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 70% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the pharmaceutical additive content is 50% by weight to 60% by weight. 
     
     
         19 . The pharmaceutical composition according to  claim 14 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         20 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         21 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         22 . The pharmaceutical composition according to  claim 15 , wherein 
 a proportion of crystals of the 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 98% or less with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition.   
     
     
         23 . The pharmaceutical composition according to  claim 22 , comprising 40 mg to 50 mg of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         24 . The pharmaceutical composition according to  claim 22 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 70% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         25 . The pharmaceutical composition according to  claim 22 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 60% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         26 . The pharmaceutical composition according to  claim 22 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         27 . The pharmaceutical composition according to  claim 22 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         28 . The pharmaceutical composition according to  claim 22 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         29 . The pharmaceutical composition according to  claim 23 , which is a tablet. 
     
     
         30 . A pharmaceutical composition for oral administration comprising:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate and a pharmaceutical additive,   wherein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 98% or less with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition,   wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate,   wherein the pharmaceutical composition exhibits a loss on drying of 2.0% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,   wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and   wherein the high-performance liquid chromatography method is performed under following conditions: 
 a Kinetex XB-C18 column, particle size:2.6 µm, 4.6 mm (an inner diameter) x 75 mm; 
 a column temperature maintained at 40° C.; 
 a mobile phase A of a perchlorate solution (pH 2.2); 
 a mobile phase B of an acetonitrile solution; 
 a sample solution having a sample concentration of 0.8 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 a standard solution having a standard solution concentration of 0.008 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and 
 a gradient of the mobile phase A and mobile phase B is as follows: 
 (a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B; 
 (b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B; 
 (c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B; 
 (d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B; 
 (e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B; 
 (f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and 
 (g) from 26.1 minutes to 30 minutes since sample injection, 96% mobile phase A and 4% mobile phase B. 
 
   
     
     
         31 . The pharmaceutical composition according to  claim 30 , comprising 40 mg to 50 mg of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         32 . The pharmaceutical composition according to  claim 30 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, Hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         33 . The pharmaceutical composition according to  claim 30 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         34 . The pharmaceutical composition according to  claim 31 , which is a tablet. 
     
     
         35 . A pharmaceutical composition for oral administration comprising:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutical additive,   wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,   wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and   wherein the high-performance liquid chromatography method is performed under following conditions: 
 a Kinetex XB-C18 column, particle size: 2.6 µm, 4.6 mm (an inner diameter) x 75 mm,; 
 a column temperature maintained at 40° C.; 
 a mobile phase A of a perchlorate solution (pH 2.2); 
 a mobile phase B of an acetonitrile solution; 
 a sample solution having a sample concentration of 0.8 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 a standard solution having a standard solution concentration of 0.008 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and 
 a gradient of the mobile phase A and mobile phase B is as follows: 
 (a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B; 
 (b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B; 
 (c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B; 
 (d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B; 
 (e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B; 
 (f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and 
 (g) from 26.1 minutes to 30 minutes since sample injection, 96% mobile phase A and 4% mobile phase B. 
 
   
     
     
         36 . The pharmaceutical composition according to  claim 35 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less. 
     
     
         37 . The pharmaceutical composition according to  claim 35 , wherein comprising 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         38 . The pharmaceutical composition according to  claim 35 , wherein a content of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 10% by weight to 40% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         39 . The pharmaceutical composition according to  claim 35 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 70% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         40 . The pharmaceutical composition according to  claim 35 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 60% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         41 . The pharmaceutical composition according to  claim 35 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         42 . The pharmaceutical composition according to  claim 35 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         43 . The pharmaceutical composition according to  claim 42 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         44 . The pharmaceutical composition according to  claim 37 , wherein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 98% or less with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition. 
     
     
         45 . The pharmaceutical composition according to  claim 44 , wherein a loss on drying of the pharmaceutical additive is 1.0% or less. 
     
     
         46 . The pharmaceutical composition according to  claim 44 , comprising 40 mg to 50 mg of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         47 . The pharmaceutical composition according to  claim 44 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight 70% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         48 . The pharmaceutical composition according to  claim 44 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 60% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         49 . The pharmaceutical composition according to  claim 44 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         50 . The pharmaceutical composition according to  claim 44 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         51 . The pharmaceutical composition according to  claim 44 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         52 . The pharmaceutical composition according to  claim 37 , which is a tablet. 
     
     
         53 . The pharmaceutical composition according to  claim 46 , which is a tablet. 
     
     
         54 . A pharmaceutical composition for oral administration comprising:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate and a pharmaceutical additive,   wherein a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 98% or less with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition,   wherein a pharmaceutical additive content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate,   wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,   wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and   wherein the high-performance liquid chromatography method is performed under following conditions: 
 a Kinetex XB-C18 column, particle size: 2.6 µm, 4.6 mm (an inner diameter) x 75 mm; 
 a column temperature maintained at 40° C.; 
 a mobile phase A of a perchlorate solution (pH 2.2); 
 a mobile phase B of an acetonitrile solution; 
 a sample solution having a sample concentration of 0.8 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamidein a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 a standard solution having a standard solution concentration of 0.008 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and 
 a gradient of the mobile phase A and mobile phase B is as follows: 
 (a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B; 
 (b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B; 
 (c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B; 
 (d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B; 
 (e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B; 
 (f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and 
 (g) from 26.1 minutes to 30 minutes since sample injection, % mobile phase A and 4% mobile phase B. 
 
   
     
     
         55 . The pharmaceutical composition according to  claim 54 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less. 
     
     
         56 . The pharmaceutical composition according to  claim 54 , comprising 40 mg to 50 mg of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate. 
     
     
         57 . The pharmaceutical composition according to  claim 54 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         58 . The pharmaceutical composition according to  claim 54 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         59 . The pharmaceutical composition according to  claim 56 , which is a tablet. 
     
     
         60 . A method of manufacturing a pharmaceutical composition for oral administration, the method comprising:
 combining 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof with a pharmaceutical additive to produce a mixture; and   granulating the mixture using fluidized bed granulation with an aqueous pharmaceutical additive solution to produce a granulated product,   wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,   wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and   wherein the high-performance liquid chromatography method is performed under following conditions: 
 a Kinetex XB-C18 column, particle size: 2.6 µm, 4.6 mm (an inner diameter) x 75 mm; 
 a column temperature maintained at 40° C.; 
 a mobile phase A of a perchlorate solution (pH 2.2); 
 a mobile phase B of an acetonitrile solution; 
 a sample solution having a sample concentration of 0.8 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 a standard solution having a standard solution concentration of 0.008 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and 
 a gradient of the mobile phase A and mobile phase B is as follows: 
 (a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B; 
 (b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B; 
 (c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B; 
 (d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B; 
 (e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B; 
 (f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and 
 (g) from 26.1 minutes to 30 minutes from injection, 96% mobile phase A and 4% mobile phase B. 
 
   
     
     
         61 . The method according to  claim 60 , further comprising:
 drying the granulated product to produce a dried product; and   optionally mixing the dried product with magnesium stearate and producing a mixture of granules; and   optionally compression-molding the mixture of granules and producing a tablet; and   optionally film-coating the tablet and producing a coated tablet.   
     
     
         62 . The method according to  claim 60 , wherein:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is combined with a pharmaceutical additive to produce a mixture; and   a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 98% or less with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition, as determined by the near-infrared spectroscopy.   
     
     
         63 . The method according to  claim 62 , further comprising:
 drying the granulated product to produce a dried product;   optionally mixing the dried product with magnesium stearate and producing a mixture of granules; and   optionally compression-molding the mixture of granules and producing a tablet; and   optionally film-coating the tablet and producing a coated tablet.   
     
     
         64 . The method according to  claim 60 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less. 
     
     
         65 . The method according to  claim 60 , wherein a content of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 10% by weight to 40% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         66 . The method according to  claim 60 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         67 . The method according to  claim 60 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 70% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         68 . The method according to  claim 60 , wherein the pharmaceutical additive content is 50% by weight to 60% by weight. 
     
     
         69 . The method according to  claim 60 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         70 . The method according to  claim 60 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         71 . The method according to  claim 60 , wherein the pharmaceutical composition is a tablet. 
     
     
         72 . A pharmaceutical composition for oral administration produced by the method according to  claim 60 . 
     
     
         73 . The pharmaceutical composition according to  claim 72 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         74 . The method according to  claim 73 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         75 . The pharmaceutical composition according to  claim 74 , which is a tablet. 
     
     
         76 . A pharmaceutical composition for oral administration produced by the method according to  claim 61 . 
     
     
         77 . The pharmaceutical composition according to  claim 76 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         78 . The method according to  claim 77 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         79 . The pharmaceutical composition according to  claim 78 , which is a tablet. 
     
     
         80 . A pharmaceutical composition for oral administration produced by the method according to  claim 63 . 
     
     
         81 . The pharmaceutical composition according to  claim 80 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         82 . The method according to  claim 81 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         83 . The pharmaceutical composition according to  claim 82 , which is a tablet. 
     
     
         84 . A method of manufacturing a pharmaceutical composition for oral administration, the method comprising:
 mixing 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof with a pharmaceutical additive to produce a mixture;   granulating the mixture using water and producing a granulated product; and   drying the granulated product using a fluidized bed granulation drier and producing a dried product,   wherein the pharmaceutical additive exhibits a loss on drying of 20% or less after storage under opened conditions of 40° C. and 75% relative humidity for 1 week,   wherein the pharmaceutical composition exhibits an increase of no more than 0.11% of an oxidative decomposition product having a relative retention time of 1.06 with respect to a retention time of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, as measured by a high-performance liquid chromatography method, after storage under opened conditions of 40° C. and 75% relative humidity for 1 month, and   wherein the high-performance liquid chromatography method is performed under following conditions: 
 a Kinetex XB-C18 column, particle size: 2.6 µm, 4.6 mm (an inner diameter) x 75 mm; 
 a column temperature maintained at 40° C.; 
 a mobile phase A of a perchlorate solution (pH 2.2); 
 a mobile phase B of an acetonitrile solution; 
 a sample solution having a sample concentration of 0.8 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 a standard solution having a standard solution concentration of 0.008 mg/ml of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide in a 4:1 mixture of the perchlorate solution (pH 2.2) and the acetonitrile solution; 
 an ultraviolet absorption spectrophotometer detector with a wavelength at 220 nm; and 
 a gradient of the mobile phase A and mobile phase B is as follows: 
 (a) from 0 minutes to 2 minutes since sample injection, 96% mobile phase A and 4% mobile phase B; 
 (b) from 2 minutes to 5 minutes since sample injection, 96% incrementing down to 85% mobile phase A and 4% incrementing up to 15% mobile phase B; 
 (c) from 5 minutes to 20 minutes since sample injection, 85% incrementing down to 68% mobile phase A and 15% incrementing up to 32% mobile phase B; 
 (d) from 20 minutes to 25 minutes since sample injection, 68% incrementing down to 30% mobile phase A and 32% incrementing up to 70% mobile phase B; 
 (e) from 25 minutes to 26 minutes since sample injection, 30% mobile phase A and 70% mobile phase B; 
 (f) from 26 minutes to 26.1 minutes since sample injection, 30% incrementing up to 96% mobile phase A and 70% incrementing down to 4% mobile phase B; and 
 (g) from 26.1 minutes to 30 minutes since sample injection, 96% mobile phase A and 4% mobile phase B. 
 
   
     
     
         85 . The method according to  claim 84 , further comprising mixing the dried product with magnesium stearate and producing a mixture of granules; and 
 optionally compression-molding the mixed of granules and producing a tablet; and   optionally film-coating the tablet and producing a coated tablet.   
     
     
         86 . The method according to  claim 84 , wherein:
 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is combined with a pharmaceutical additive to produce a mixture; and   a proportion of crystals of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate is 98% or less with respect to a total amount of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate in the pharmaceutical composition.   
     
     
         87 . The method according to  claim 86 , further comprising:
 drying the granulated product to produce a dried product; and   optionally mixing the dried product with magnesium stearate and producing a mixture of granules; and   optionally compression-molding the mixture of granules and producing a tablet; and   optionally film-coating the tablet and producing a coated tablet.   
     
     
         88 . The method according to  claim 84 , wherein the loss on drying of the pharmaceutical additive is 1.0% or less. 
     
     
         89 . The method according to  claim 84 , wherein a content of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 10% by weight to 40% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         90 . The method according to  claim 84 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         91 . The method according to  claim 84 , wherein a pharmaceutical additive content in the pharmaceutical composition is 50% by weight to 70% by weight with respect to 100% by weight of the pharmaceutical composition. 
     
     
         92 . The method according to  claim 84 , wherein the pharmaceutical additive content is 50% by weight to 60% by weight. 
     
     
         93 . The method according to  claim 84 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         94 . The method according to  claim 84 , wherein the pharmaceutical additive is lactose or D-mannitol. 
     
     
         95 . The method according to  claim 84 , wherein the pharmaceutical composition is a tablet. 
     
     
         96 . A pharmaceutical composition for oral administration produced by the method according to  claim 84 . 
     
     
         97 . The pharmaceutical composition according to  claim 96 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         98 . The method according to  claim 97 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         99 . The pharmaceutical composition according to  claim 98 , which is a tablet. 
     
     
         100 . A pharmaceutical composition for oral administration produced by the method according to  claim 85 . 
     
     
         101 . The pharmaceutical composition according to  claim 100 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         102 . The method according to  claim 101 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         103 . The pharmaceutical composition according to  claim 102 , which is a tablet. 
     
     
         104 . A pharmaceutical composition for oral administration produced by the method according to  claim 87 . 
     
     
         105 . The pharmaceutical composition according to  claim 104 , wherein the pharmaceutical additive is selected from the group consisting of lactose, D-mannitol, anhydrous dibasic calcium phosphate, talc, calcium stearate, magnesium stearate, microcrystalline cellulose, hydroxypropyl cellulose, hypromellose, corn starch, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. 
     
     
         106 . The method according to  claim 105 , wherein a pharmaceutical additive weight content in the pharmaceutical composition is 1.5 times to 4.5 times that of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or the pharmaceutically acceptable salt thereof. 
     
     
         107 . The pharmaceutical composition according to  claim 106 , which is a tablet.